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2002 Selected Articles

Management of Asthma in Pregnancy

Vidyashankar B. Revan, MD; Eleanor Y. Sun, MD; Marc S. McMorris, MD

Asthma is a common disorder among women of childbearing age, affecting approximately 7% of this population.¹ Between 1% and 4% of pregnant women present with asthma that requires medical management. Pregnancy can have variable effects on the course of asthma, ie, asthma symptoms improve in 33% of pregnant women, worsen in 33%, and remain unchanged in 33%. These effects typically reach a peak at 24 to 36 weeks’ gestation.

Understanding the management of asthma during pregnancy is particularly important for the primary care physician and obstetrician in view of the potential effects of asthma and asthma treatments on the mother and the developing fetus. Poorly controlled asthma can lead to fetal hypoxia, hypocapnia, and low birthweight.

RESPIRATORY PHYSIOLOGY IN PREGNANCY

The management of asthma in pregnancy must take the normal changes occurring in respiratory physiology during gestation into consideration. In healthy pregnant women, minute ventilation increases by 50% (possibly due to progesterone-mediated effects),² oxygen consumption and carbon dioxide (CO₂) production increase, and arterial blood gas analysis shows a compensated respiratory alkalosis. However, despite changes in body habitus, total lung capacity, vital capacity, forced expiratory volume at 1 second (FEV₁), the ratio of FEV₁ to forced vital capacity (FVC), and peak expiratory flow rate (PEFR) do not change significantly, although FEV₁ and PEFR may decrease in the supine position.² Functional residual capacity often declines in late pregnancy due to decreases in both expiratory reserve volume (ERV) and residual volume (RV).²

Some pregnancy-related physiologic changes may improve asthma symptoms. Natural bronchodilatation may increase due to alterations in native factors such as progesterone, atrial natriuretic factor, and prostaglandin E. Bronchodilator effectiveness may improve due to an estrogen-mediated potentiation of b-adrenergic responsiveness, higher levels of native glucocorticoids, prolonged bronchodilator half-life, and decreased protein-binding of bronchodilators. Bronchoconstriction tends to be reduced due to lower levels of plasma histamine and prostaglandin I₂-mediated bronchial stabilization.

However, there are also physiologic changes during pregnancy that can exacerbate asthma symptoms. Pulmonary refractoriness to cortisol effects can develop due to competitive binding to glucocorticoid receptors by progesterone, aldosterone, or deoxycorticosterone. Increased levels of prostaglandin F₂ can lead to bronchoconstriction, and higher amounts of placental major basic protein reaching the lung can aggravate asthma. Pregnant asthmatics may be more susceptible to respiratory infections because of immune system changes, and pregnancy-related gastroesophageal reflux disease (GERD) and stress can also intensify symptoms.

MANAGEMENT

Principles and Goals

The principal goal of asthma management during pregnancy is to optimize fetal health while minimizing the adverse effects of therapy. Other goals include achieving normal pulmonary function and maternal-fetal oxygenation, controlling symptoms (including nocturnal symptoms), maintaining normal effort tolerance, and avoiding acute exacerbations and severe attacks. This can be accomplished by asthma trigger avoidance and appropriate medical treatment.

Nonpharmacologic Therapies

Environmental control measures to reduce exposure to asthmatic triggers are important for all patients. Smoking is an important trigger for asthma. According to the Third National Health and Nutrition Examination Survey, 23% of mothers smoke during pregnancy.³ Fetal levels of tobacco toxins that cross the placenta such as carbon monoxide (CO), nicotine, and cyanide exceed levels of maternal exposure. Babies born to smokers tend to have a lower birthweight by an average of 200 g. In addition, pregnant smokers who have severe, uncontrolled asthma have a higher incidence of spontaneous abortion, placental abnormalities, preterm birth, and perinatal death. Smoking may also lead to abnormal lung development in utero.³

Patients with asthma often have environmental allergies, and must minimize exposure to offending allergens. Recommendations include using dust-mite and allergen-proof mattress and pillow casings, frequent laundering of clothes and sheets, and vacuuming with double-thickness or high-efficiency particulate air (HEPA) filter bags. Pet dander exposure can be minimized by keeping animals out of the bedroom, utilizing air filters, washing pets weekly, and removing potential reservoirs of pet allergens (eg, carpets, drapes, upholstery). Air conditioners and dehumidifiers help decrease mold allergens.⁴ Preconception counseling should include these recommendations, as well as educating potential parents that creating a low-dust-mite, pet-free home may reduce the risk of asthma in their children.

Pharmacotherapy

Nonpharmacologic interventions such as environmental control measures, although important, rarely provide complete symptomatic control of asthma/allergies in pregnancy. Patients usually require asthma medications. The risk of using newer therapeutic options, for which human pregnancy data are not yet adequate, has to be weighed against the use of older medications that may not fully control symptoms. Medications can cause side effects such as nausea and drowsiness, and can have adverse effects on the fetus, including teratogenicity and intrauterine growth retardation. Specifically, β agonists can raise blood pressure and heart rate, while steroid use may increase the risk of preeclampsia and low birthweight.^2,5 Despite these potential side effects, however, studies noted no increase in perinatal mortality when asthma was managed by specialists.⁶ Thus, the benefits of careful management of asthma in pregnancy clearly outweigh the risks of undertreatment due to fears of adverse drug effects.

The US Food and Drug Administration (FDA) pregnancy risk categories are used as a guide by many clinicians in prescribing medications in pregnancy (Table 1). These recommendations are mainly based on animal studies, and the FDA recognizes that these categories are inadequate and sometimes misleading. Choosing a therapy based solely on the FDA categories may result in the use of less effective medications. For example, the newer leukotriene receptor antagonists are classified as Category B, while other effective drugs that have been used for many years during pregnancy with few significant problems (eg, prednisone, inhaled corticosteroids, theophylline) are classified as Category C. Public hearings are underway to consider an alternative to the current labeling system.⁷ Several classes of asthma medications are useful in pregnancy; in general, a stepped approach to asthma management is wisest (Tables 2 and 3).

Antihistamines.–Antihistamines can be used during pregnancy in patients whose asthma is triggered by allergies. As antihistamines can have a drying effect on the bronchial mucosa, their use in asthma was discouraged when they were introduced. However, these concerns were more theoretical than practical, and newer antihistamines have proved beneficial in asthmatics.² These drugs have been shown to reduce asthma symptoms, improve pulmonary function, and enhance quality of life.²

Antihistamines that can be used in pregnant asthmatics include chlorpheniramine and tripelennamine; the FDA has not yet classified these drugs, but animal studies have shown no teratogenicity and they have a long history of use plus reassuring animal and human data.^8,9 Second-generation antihistamines such as loratadine (Category B) or cetirizine (Category B) should be reserved for patients in whom other antihistamines cause sedation.

Oral antihistamines should be avoided during the first trimester unless there is medical justification, such as substantial quality-of-life issues. If the patient is using alternative antihistamines that lack pregnancy data at the time of conception, the mother can be reassured that there is little likelihood of major congenital defects.

β-Agonists.–These drugs are the mainstay of asthma therapy, and they are used across the spectrum from mild, intermittent asthma to severe, persistent cases. Terbutaline (Category B), metaproterenol (Category C), and albuterol (Category C) are older agents with more data to support their use in pregnancy. The inhaled route is recommended for b-agonists, as this minimizes systemic effects. However, when subcutaneous or oral administration is indicated, terbutaline is preferred due to reassuring animal data.¹⁰ Epinephrine has shown a potential for teratogenicity in animal studies and alternative nebulized agents are available, but epinephrine remains the drug of choice for anaphylaxis.¹⁰

Salmeterol.–No human data have been published regarding the use of salmeterol during pregnancy. Animal studies with systemically administered salmeterol are not reassuring, but inhaled salmeterol use in humans, plus the experience with short-acting albuterol (animal studies suggesting adverse effects, but human data reassuring), suggest that the animal data may not be predictive of human risk. Salmeterol would not generally be recommended for use during pregnancy in preference to the older β₂ agonists, cromolyn and beclomethasone, but risk-benefit considerations may favor its continuation during pregnancy in patients with moderate or severe asthma who have demonstrated a very good therapeutic response preconception.¹¹

Ipratropium.–Nebulized ipratropium (Category B) is useful in patients who cannot tolerate β₂ agonists or with an inadequate response to adjunctive inhaled β₂ agonist therapy for bronchodilation in acute asthma. No human data are available, but animal findings are reassuring.

Theophylline.–Theophylline (Category C) is prescribed less frequently than other agents, but it has a long track record of use in pregnancy. It can be considered for patients requiring therapy in addition to inhaled b-agonists and corticosteroids. Sustained-release theophylline is preferred; the target blood level should be in the low end of the therapeutic range (5 to 12 µg/mL) to minimize the risk of toxicity.^12,13

Mast Cell Inhibitors.–Inhaled nedocromil and cromolyn sodium both are Category B agents. They have no significant side effects and a long safety record, especially in the case of cromolyn sodium. They can be continued in pregnancy if a good response was noted preconception, and if the mother is reluctant to use inhaled corticosteroids. These medications are not useful in acute attacks.

Corticosteroids.–Inhaled corticosteroids are accepted as the most effective anti-inflammatory medication for long-term control of persistent asthma.^14,15 Beclomethasone and budesonide are recommended during pregnancy because more data are available on their safety. Beclomethasone, flunisolide, triamcinolone, and fluticasone are classified as Category C, and budesonide was recently upgraded to Category B. Use of inhaled corticosteroids has led to decreased acute asthma episodes and hospitalization. Studies of completed pregnancies where inhaled corticosteroids were used have shown no significant changes in birthweight or in the incidence of birth defects.¹⁶

Oral and systemic corticosteroid trials have demonstrated safety in short-term, high-dose "bursts." One study did note an increased incidence of cleft palate with oral steroid use in the first trimester¹⁷ and a higher risk of preeclampsia has been reported in several studies with oral corticosteroids, but there are insufficient data to differentiate between effects of medication and those of severe asthma.¹⁸ Long-term systemic corticosteroid use carries the risk of significant hyperglycemia and its associated risks, including macrosomia. However, in patients with a high risk of status asthmaticus, the benefits of appropriate systemic corticosteroid use for severe asthma far outweigh the presumed risks of direct adverse effects on the mother and baby.

Leukotriene Modifiers.–These newer medications are useful as monotherapy in mild asthma or as supplemental therapy in more severe cases. Adequate human data on their effectiveness and safety in pregnancy are not yet available, but animal studies are reassuring on the safety of montelukast. Both montelukast and zafirlukast are classified as Category B. Zileuton, a lipooxygenase inhibitor, is Category C due to associations with fetal abnormalities in animal studies.

Immunotherapy.–Allergy shots are an effective form of therapy for both allergic rhinitis and allergic asthma.¹⁹ Indeed, immunotherapy and allergen avoidance are the only therapeutic measures that have the potential to modify the natural course of these conditions. Immunotherapy should not be initiated, nor the dose increased, during pregnancy to reduce the risk of anaphylaxis. However, maintenance immunotherapy can be continued if there are no ongoing problems. Skin testing is generally avoided during pregnancy.

Immunizations.–Influenza vaccine is safe in pregnancy, and should be administered during the second and third trimesters. Theophylline levels should be monitored following vaccination because of reports of prolongation of half-life in some asthmatic children with influenza and the consequent risk of raising theophylline levels above therapeutic levels.^5,20 Pneumonia vaccination is not recommended during pregnancy, but patients with severe asthma who are contemplating pregnancy should consider preconception vaccination. Table 4 summarizes the Asthma and Pregnancy Working Group recommendations regarding medication use.

GERD

This is common during pregnancy, and it is a known trigger of asthma. The presence of gastric acid in the esophagus causes bronchoconstriction by complex neurogenic mechanisms. Nonpharmacologic antireflux measures are essential, but if nonpharmacologic measures fail, the drug of choice for GERD in pregnancy is ranitidine (Category B), although all histamine (H₂) blockers except nizatidine appear safe based on animal studies. In a recent report on omeprazole, a proton pump inhibitor, there was no significant effect on the incidence of major fetal malformations.⁶

Acute Asthma

The clinician must first assess the patient’s general appearance, vital signs, and oxygenation to determine the severity of the asthma attack and the need for more aggressive monitoring in the emergency department or for hospital admission. Close maternal monitoring and aggressive medical management are essential if the pulse rate exceeds 120 beats/min, the pulsus paradoxus is more than 12 mm Hg, pulse oximetry is less than 95%, the partial oxygen pressure (PO₂) falls below 70 mm Hg, and the partial CO₂ pressure (PCO₂) is above 35 mm Hg. Fetal heart-rate monitoring for decelerations and absence of beat-to-beat variability is critical as well. Recommendations for pharmacologic management of acute asthma in pregnancy and labor are summarized in Tables 5 and 6, respectively.²¹

Obstetric Management

For well controlled, mild, and moderately controlled asthmatics, obstetric management is no different from that in pregnant nonasthmatics. For poorly controlled asthmatics, or those requiring frequent oral glucocorticoids, careful monitoring for intrauterine growth retardation and preeclampsia is needed.

Medications.–Medications with obstetric indications that can trigger bronchospasm in asthmatics should be avoided. Examples include β-blockers, 15-methyl prostaglandin F_2α, transcervical or intraamniotic prostaglandin E₂, methylergonovine or ergonovine, and nonsteroidal anti-inflammatory drugs (NSAIDs) in aspirin-sensitive asthmatics.²

The use of intravaginal and intracervical prostaglandin E₂ gel for cervical ripening before labor induction, or prostaglandin E₂ suppositories for therapeutic abortion or labor induction with a dead fetus, have not been reported to cause bronchospasm. Magnesium sulfate and calcium-channel blockers have been shown to have bronchodilator properties, and should be well tolerated in asthmatic subjects.²

Anesthesia.–Regional anesthesia is preferred over general anesthesia during delivery. If general anesthesia is required, medications with bronchodilating properties are recommended, eg, preanesthetic atropine or glycopyrrolate, induction with ketamine or low concentrations of halogenated anesthetics. Typically, induction of anesthesia in the asthmatic patient is the same as in the nonasthmatic. The patient should use her current bronchodilator medication prior to induction.

Postnatal Period

Adrenal insufficiency has only rarely been reported in infants of mothers receiving glucocorticoids during pregnancy. Consequently, although such infants should be observed carefully by a perinatologist for evidence of adrenal hypofunction, prophylactic treatment is not warranted.

CONCLUSION

Asthma is common in pregnancy. Poorly controlled asthma can be deleterious to both mother and fetus, but appropriate treatment that produces good control will minimize the risks. There is a wide range of effective treatments for asthma in pregnancy, most of which are well tolerated and have a reasonable risk-benefit ratio. Pregnancy should not deter clinicians from appropriate asthma management. The recommendations made in this article are not meant to be absolute, but rather are presented to serve as guidelines. They must be adapted for the individual patient, and should be subject to modification as additional information becomes available.

Vidyashankar B. Revan, MD, is a fellow, Department of Internal Medicine, Division of Allergy and Clinical Immunology, University of Michigan Health Systems, Ann Arbor. Eleanor Y. Sun, MD, is a clinical instructor, Department of Internal Medicine, Division of General Medicine, Ann Arbor Health Center, University of Michigan Health System, Ann Arbor. Marc S. McMorris, MD, is a clinical assistant professor of allergy and clinical immunology, Department of Internal Medicine, Division of Allergy and Clinical Immunology, and clinical assistant professor, Department of Pediatrics and Communicable Diseases, both at the University of Michigan Health Center in Ann Arbor.

REFERENCES

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21. National Asthma Education Program Highlights of the Expert Panel Report 2. Guidelines for the Diagnosis and Management of Asthma. Pub. No. 97-4051, Bethesda, MD, 1997.

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